The invention relates to the loading process of a target volume with ions of different mass but same energy from a somewhat distant ion storage device inside a mass spectrometer. The loading process normally exhibits an often undesirable mass dispersion. The target volume can be, for example, the measuring cell of an ion cyclotron resonance mass spectrometer (ICR-MS), the pulser of a time-of-flight mass spectrometer with orthogonal ion injection (OTOF) or an electrostatic ion trap.
Ion cyclotron resonance mass spectrometers have a measuring cell 65 which is located far away from the ion source 61 in the interior of a strong magnetic field produced by a magnet field generator 66, as shown in FIG. 1. The ions of the ion source are generally collected in an intermediate storage device outside the magnetic field and then transferred into the measuring cell at the beginning of a measuring cycle. The transfer takes place collision-free in an ion beam. The ions are, in principle, free-flying but can also be guided along the path by an ion guide. It is a well-known fact that it is difficult to capture the ions in the measuring cell; it would be very favorable if the ions of all masses could enter in a small ion bunch synchronously the measuring cell with the same low energy of only fractions of an electron-volt. Specialists in the filed are familiar with the details of this problem. The ions are prevented from entering at the same time, however, by the different flight velocities of the ions of different masses between the storage device and measuring cell, resulting in a mass dispersion. This mass dispersion can be reduced by strongly accelerating the ions from the storage device and strongly decelerating them before they enter the measuring cell, but it cannot be eliminated completely.
The ions must also be focused into a narrow ion beam so that they can be threaded into the strong magnetic field, a process which is carried out in axial direction through the fringe field of the magnet. Ions somewhat outside the axis of the fringe field are first wound up into increasingly narrow spirals by the fringe field, as in a magnetic bottle, and then reflected.
Similar problems with mass dispersion also occur when electrostatic ion traps have to be filled, such as Kingdon-type ion traps. The ions are held in orbits by radial electric fields in these electrostatic ion traps. The ions are injected with the same energy into an orbit through an electrically switchable input region. The filling must be completed before the fastest, i.e. the lightest ions pass the injection point again after having completed one orbit because the potentials then must have be changed from injection mode back to orbit conditions. As far as possible, the ions of all masses must enter the electrostatic ion trap at the same time; on no account must heavy ions enter later than light ions. Also here, a narrow ion beam is favorable for ion injection.
Mass dispersion also disturbs time-of-flight mass spectrometers with orthogonal ion injection when the ions are being injected from a storage device into the ion pulser which pulse ejects the ions into the flight path. The mass dispersion leads here to a mass discrimination of the spectrometer.
In all these cases, there is usually a collision gas in the storage device which serves to collision focus and cool the ions. The ions can then readily collect in the axis of the storage device and have a very narrow energy spread. The above-described target volumes, on the other hand, all must be positioned in regions with a very good vacuum in order to prevent the ions undergoing any collisions with molecules of residual gas. The ions therefore usually have to pass, between storage device and target volume, through one or more differential pump stages. The ions are transferred from the storage device to the target volume by collision-free flight, at least with as few collisions as possible, after they have been accelerated out of the storage device.
Different technical areas of mass spectrometry thus suffer a similar problem which occurs when ions are transferred from a storage device into a distant target volume and primarily consists in the mass dispersion of ions with different mass but equal energy. The ions of different mass have different velocities and therefore arrive at the target volume in a velocity-dependent order which, depending on the purpose of the target volume, can lead to problems. A wide distance between the storage device and the target volume to be filled is often unavoidable; it is usually enforced by the requirement to have differential pumping between the storage device and the target volume to be filled, but it can also be necessary because of other situations, for example the long starting path into a strong magnetic field. A secondary problem lies in the fact that a narrow ion beam must be formed.
These situations will be explained here in a little more detail using the example of a time-of-flight mass spectrometer, although the problem-solving idea of the invention described below shall not be solely limited to the situation in this time-of-flight mass spectrometer.
The term “mass” here always refers to the “charge-related mass” m/z, also called “mass-to-charge ratio”, and not simply to the “physical mass” m. The dimensionless number z is the number of elementary charges of the ion, i.e. the number of excess electrons or protons which the ion possesses and which act externally as the ion charge. All mass spectrometers without exception measure only the charge-related mass m/z and not the physical mass m itself. The charge-related mass is the mass fraction per elementary ion charge. The terms “light” and “heavy” ions here are always analogously understood as being ions with low or high charge-to-mass ratio m/z respectively. The term “mass spectrum” also always relates to the mass-to-charge ratios m/z.
Time-of-flight mass spectrometers where a primary ion beam is injected orthogonally to the flight path are termed OTOF (orthogonal time-of-flight mass spectrometers). FIG. 2 illustrates an OTOF of this type. They have a so-called pulser (11) at the beginning of the flight path (19) which accelerates a section of the primary ion beam (10), i.e. a string-shaped ion package, into the flight path (19) at right angles to the previous direction of the beam. This causes a band-shaped secondary ion beam (12) to form, which is comprised of individual string-shaped ion packages lying transversely, consisting of ions with the same mass. The string-shaped ion packages with light ions fly quickly; those with heavier ions fly more slowly. The direction of flight of this band-shaped secondary ion beam (12) is between the previous direction of the primary ion beam and the direction of acceleration at right angles to this because the ions retain their velocity in the original direction of the primary ion beam (10). A time-of-flight mass spectrometer of this type is preferably operated with a velocity-focusing reflector (13) which reflects the whole width of the band-shaped secondary ion beam (12) with the string-shaped ion packages and directs it toward a detector (14) which is likewise flat.
As can be seen in FIG. 2 and in the detailed representation of the injection regime in FIG. 3, the ions of the primary ion beam (10) are accelerated in the pulser (11) at right angles to the direction in which they are injected, the x-direction. The direction of acceleration is called the y-direction. The direction of the resulting ion beam (12) is between the y-direction and the x-direction, since the ions retain their original velocity in the x-direction. The angle between the ion beam (12) and the y-direction is α=arctan (vx/vy), where vx is the velocity of the ions in the primary beam in the x-direction and vy is the velocity component of the ions after they have been accelerated in the y-direction. The angle α is exactly the same for ions of different masses when they all fly with the same kinetic Energy Ex into the pulser because they all receive the same additional kinetic Energy component Ey, and vx/vy is proportional to √(Ex/Ey). Thus the flight direction of the ions in the ion beam (12) after they have been ejected as a pulse does not depend on the mass of the ions if all ions of the original ion beam (10) had the same kinetic energy Ex, i.e. all were accelerated with the same voltage difference in the x-direction.
The pulser (11) operates at pulsing rates between 5 to 20 kilohertz depending on the desired mass range of the spectrometer. If one considers a time-of-flight mass spectrometer which operates at 10 kilohertz, then 10,000 individual mass spectra are acquired per second which, in modern time-of-flight mass spectrometers, are digitized in a transient recorder and added together to form sum spectra. A mass spectrum here can quite easily contain mass signals with around 1,000 ions before one needs to worry about saturation of the electronic components in the detector. (Older time-of-flight mass spectrometers operate with event counters or time-to-digital converters but have only a narrow dynamic range of measurement since the dead times mean that they can identify only a single ion in each mass peak). It is possible to set the length of time over which the transient recorder adds the spectra: the summing time can be a twentieth of a second, in which case around 500 individual mass spectra can be added to form a sum spectrum. But the addition can also be carried out over a hundred seconds and encompass a million individual mass spectra in the sum spectrum. This latter sum spectrum then has a very high dynamic measuring range of about eight orders of magnitude for the measurement of the ions in the spectrum.
The ions whose mass spectrum is to be measured are not generally a homogeneous ionic species but rather a mixture of light, medium and heavy ions. The mass range here can be very broad. In protein digest mixtures, for example, the mass range of interest extends from the lightest immonium ion up to peptides with around 40 amino acids, i.e. from a mass of 50 Daltons to around 5,000 Daltons. In time-of-flight mass spectrometers for the elemental analysis of metals or organic materials with ionization by inductively coupled plasma (ICP), the mass range of interest is between 5 Daltons (analysis of lithium) up to roughly 250 Daltons (analysis of uranium and transuranic elements). To obtain quantitatively good analytical results there should be no mass discrimination over these wide mass ranges.
In the time-of-flight mass spectrometer in FIGS. 2 and 3, the primary ion beam is extracted from an RF ion guide (8), which serves here as the storage device, with the aid of a lens system (9) and injected with a low energy of only around 20 electron-volts into the emptied pulser (11). The primary ion beam (10) here must be positioned extremely accurately and also reproducibly in the pulser. However, a primary ion beam (10) with an energy of 20 electron-volts is extraordinarily sensitive to external electric or magnetic influences; it therefore has to be shielded with a casing (18) which has very good electrical conductivity. There are two modes of operation here: continuous and pulsed. In continuous mode, the primary ion beam (10) is not interrupted; it flows continuously toward the pulser (11). After the pulsed ejection, the pulser (11) is again returned to voltages which enable it to be refilled, and so the pulser (11) again fills with ions. However, in the vicinity of the pulser (11), the process of pulsed ejection greatly interferes with the primary beam (10) far into the shielding casing (18); it therefore takes a while until the undisturbed primary beam (10) is accurately and correctly positioned so as to be able to fill the pulser (11) again. For this reason a pulsed mode is normally chosen, in which the primary beam (10) to the pulser (11) is interrupted by means of a switchable lens (9) and the beam is only enabled for filling again when the potentials have stabilized after the electrical switching process. This makes it possible to slightly increase the duty cycle for the measurement of the ions.
Between the storage device and pulser, differential pumping must occur and the ion beam must also be well-shielded by the casing (18); there has to be a spatial separation between the storage device and pulser. The process of injecting the ions into the pulser therefore discriminates according to mass. If this injection process for the pulser (11) is interrupted after a short time by pulsed ejection of the ions into the flight path (20), very light ions of the primary ion beam (10) have already reached the end of the pulser (11), medium mass ions have only penetrated a short way into the pulser (11), while heavy, and hence slow, ions have not even reached the pulser (11). The pulse-ejected ion beam (12) thus contains only light and a few medium-mass ions. There are no heavy ions at all. For a very long injection time, on the other hand, during which the heavy ions have penetrated to the end of the pulser (11), these heavy ions are predominant in the pulse-ejected ion beam (12) since the high velocity of the medium-mass and light ions means that most of them have already left the pulser (11) again.
The diagram in FIG. 4 illustrates this behavior. A quadrupole rod system (8) some 8 centimeters in length with a switchable lens (9) at the end is used as the ion storage device. In this graph, the time delay t (in microseconds) between the pulsed ejection of the ions from the pulser (11) and the opening time of the switchable lens (9) is plotted on the horizontal axis, and the logarithm of the ion current for ions of different masses forms the vertical axis. The dynamic range of measurement is not selected so as to be very high here; it is somewhat higher than four powers of ten. It can be seen that the ions with a mass of 322 Daltons fill the pulser optimally after only 30 microseconds, whereas the ions with a mass of 2722 Daltons need around 160 microseconds to reach their maximum intensity in the pulser. If heavy ions are to be detected, this can only be done using a measuring mode with a delay time for the pulsed ejection of around 160 microseconds. The light ions are then already at around 10% of their maximum intensity, however, simply because the storage device (8) is continuously filled with more ions through the lens (7), said ions simply passing through the storage device (8). This limits the rate of spectrum acquisition to a maximum of 6 kilohertz. The mass spectrum in FIG. 5 was acquired with this conventional method and a delay time of 160 microseconds: The mass spectrum shows a mixture of substances which are usually used to calibrate mass spectrometers.
Time-of-flight mass spectrometers with orthogonal ion injection can only ever operate within limited mass ranges since, on the one hand, the ion guide (6) and storage device (8) always create lower (and upper) mass limits and, on the other, the acquisition rate imposes a maximum duration for the spectrum acquisition and hence for the upper limit of the mass range measured. In general, it is possible to set several operating mass ranges in this type of time-of-flight mass spectrometer, for example 50 to 1,000 daltons, 200 to 3,000 daltons or 500 to 10,000 daltons. The conditions for the ion guides and storage devices and the acquisition rate are then adapted to the operating mass ranges.
When the time-of-flight mass spectrometer is operated according to the prior art, as is shown in FIGS. 2, 3 and 4, there is thus an optimum delay between the opening time of lens (9) and the pulsed ejection of the pulser (11) for the detection sensitivity of ions of a specific mass within the operating mass range which has been set for the time-of-flight mass spectrometer. This has already been elucidated in principle in U.S. Pat. No. 6,285,027 B1 (I. Chernushevich and B. Thompson). A preferred internal mass range with maximum sensitivity can be set via the opening time of the lens (9), the duration of injection into the pulser (11) and the ejection time, although this inevitably discriminates against ions of other masses in the operating mass range set. The delay time can be controlled via the electrical configuration of the switchable lens (9) and the pulser (11). This mode of operation where a mass has always to be selected, for which an optimum sensitivity is achieved, is very impractical for an analytical method, however, and difficult to perform in practice.
The energy of the injected ions in the primary ion beam (10) basically represents a further parameter. However, this energy of the injected ions is usually not adjustable, or adjustable only within very narrow limits which are determined by the geometry of the time-of-flight mass spectrometer, and in particular by the distance between pulser (11) and detector (14), depending on the overall flight distance in the time-of-flight mass analyzer. This distance determines the angle of deviation α explained above which must be maintained in order to operate the mass spectrometer, otherwise the ions do not impinge directly onto the detector.
The energy spread of the ions must be very narrow to fill the pulser in the time-of-flight mass spectrometer, otherwise the ions enter the flight path at different angles of deviation α and not all of them impinge onto the detector. For other target volumes as well, for example for filling the measuring cell in the ICR mass spectrometer, it is important that the energy spread of the ions is very narrow.
The use of traveling field effects in so-called “traveling wave guides” makes it possible to inject ions of different masses simultaneously into the pulser (11) because this imparts the same velocity to all ions, see also “An Investigation into a Method of Improving The Duty Cycle on OA-TOF Mass Analyzers”, S. D. Pringle et al., Proc. of the 52nd ASMS Conference on Mass Spectrometry and Allied Topics, Nashville, May 23-27, 2004, or “Applications of a traveling wave-based radio-frequency-only stacked ring ion guide”, K. Giles et al., Rapid Commun. Mass Spectrom. Since the ions of different masses have different kinetic energies, they are all pulse-ejected from the pulser (11) at different angles of ejection a for the ion beam (12), which means that not all of them arrive at the detector (14). The mass discrimination now occurs at the detector (14) and no longer in the pulser (11).
A further option for compressing the ions clouds of different masses is described in the paper “A Novel MALDI Time of Flight Mass Spectrometer” by J. F. Brown et al., 53rd ASMS Conference on Mass Spectrometry and Allied Topics, 2005, although in this case the ions in the pulser do not have the same energy so that the mass discrimination is again shifted to the detector.
The injection method for the pulser (11) at a given energy of the ions in the primary ion beam (10) must be optimized not only with respect to starting time and duration. It is also necessary to generate a narrow primary ion beam (10) of optimal cross section so that the time-of-flight mass spectrometer has a high resolution. If all ions fly one behind the other precisely in the axis of the pulser (11), and if the ions have no velocity components transverse to the primary ion beam (10), then theoretically, as can be easily understood, it is possible to achieve an infinitely high mass resolution because all ions of the same mass fly as almost infinitely thin ion strings exactly in the same front and impact onto the detector (14) at precisely the same time. If the primary ion beam (10) has a finite cross section, but no ion has a velocity component transverse to the direction of the primary ion beam (10), it is again theoretically possible to achieve an infinitely high mass resolution by space-focusing in the pulser (11) in the familiar way. The high mass resolution can even be achieved if there is a strictly proportional correlation between the location of the ion (measured from the axis of the primary beam in the direction of the acceleration, i.e. in the y-direction) and the transverse velocity of the ions in the primary beam (10) in the direction of the acceleration. If no such correlation exists, however, that is if the locations of the ions and the transverse velocities of the ions are statistically distributed with no correlation between the two distributions, then it is not possible to achieve a high mass resolution.
In addition to optimizing the injection process with respect to the mass range of the ions supplied, it is thus also necessary to condition the ions in the primary ion beam (10) with respect to their spatial and velocity distribution in order to achieve a high mass resolution in the time-of-flight mass spectrometer. To condition the ion beam in this way, ions which have been well thermalized by undergoing collisions in the neutral collision gas must be extracted in a very narrow beam from the axis of the storage device (8) by a very good ion-optical lens system (9).
Storage devices generally take the form of multipole RF rod systems filled with collision gas and terminated at both ends with diaphragms or lens systems with an ion-repelling potential. The rod systems are usually either quadrupole or hexapole systems. The ions lose their kinetic energy in collisions with the collision gas and collect in the minimum of the pseudopotential, i.e. in the axis of the rod system. This process is called “collision focusing”. The pseudopotential minimum for light ions is more pronounced and steeper than for heavy ions, so the light ions collect precisely in the axis and the heavier ions more to the outside, kept apart by the Coulomb repulsion of the light ions. This effect is only observed when filling with large numbers of ions, however. In normal operation, a time-of-flight mass spectrometer is filled with a few thousand ions or so; usually only a few hundred ions. At these levels, the mass-selective arrangement of the ions in the storage device is not yet measurably effective.
In rod systems with more than three rod pairs (octopole, decapole or dodecapole rod systems) the minimum of the pseudopotential in the axis is not so pronounced, and the ions, repelled by their own space charge, can also collect outside in front of the rods. It is then more difficult to draw out the ions as a fine beam close to the axis.
If the storage devices take the form of rod systems whose pole rods are arranged in parallel, then they are also termed “linear ion traps”, in contrast to so-called “three-dimensional ion traps”, which comprise ring and end cap electrodes. Rod systems with two or three pairs of rods which generate quadrupole or hexapole fields in the interior make particularly good storage devices. It should be noted, however, that three-dimensional ion traps can also be used as storage devices. There are also completely different systems which can likewise be used as storage devices, for example quadrupole or hexapole stacks of plates as described in the patent application publication DE 10 2004 048 496 A (C. Stoermer et al., equivalent to GB 2 422 051 A and US-2006-0076485-A1). These plate stacks can create a potential gradient in the interior along the axis, making it possible to expel ions quickly from the storage device. Something similar also applies to ion storage devices made of coiled pairs of wires, as in patent DE 195 23 859 C2 (J. Franzen, equivalent to U.S. Pat. No. 5,572,035 A and GB 2 302 985 B).
The pressure in the storage device amounts generally to values between 0.01 and 1 Pascal. The vacuum pressure in the pulser and in the flight path (19) of the time-of-flight mass spectrometer must be maintained very low, however, preferably at a value below 10−4 Pascal. This requires that the lens system (9) also acts as a barrier for the collision gas and that there must be differential pumping between the storage device and pulser. The lens system therefore either has to incorporate a diaphragm with a very fine aperture, for example only around 0.5 millimeters, or must itself undergo an intermediate evacuation, i.e. it must be constructed as a differential pressure stage.
If it were possible to transport all the thousand ions of one filling of the storage device to the detector with no losses and measure them, then an operating rate of 10 kilohertz would enable ten million ions to be measured per second without mass discrimination. The dynamic range of measurement for spectral scans of one second's duration would be around 1:1,000,000. These values cannot be achieved with the mode of operation usually used hitherto.